Levodopa (LD) is the most effective drug for the symptomatic treatment of Parkinson's disease (PD). No other medical or surgical therapy currently available has been shown to provide anti-Parkinson benefits superior to what can be achieved with LD. However, following few years of LD treatment, the actions of each dose tend to wear off in the majority of PD patients. This wearing off between doses is strongly correlated to the drug's peripheral pharmacokinetic (PK) profile. The patients may find themselves during the day in either ON state, when the patients are capable of normal movement, or in OFF state, wherein the patients suffer from impaired movement. As the disease progresses, the patients begin to fluctuate between the two states. These fluctuations are often accompanied by troublesome diskinesias in ON state and deep OFF state, wherein movement is severely impaired. Hence, improving consistency of LD's plasma levels is essential for improving its anti-Parkinson effects.
In addition, in current treatment, physicians fractionate LD doses in an attempt to reduce the pulsed action of fewer, larger doses, and to stabilize the LD's pharmacokinetic (PK) profile. Hence, a significant pill burden is another major concern, associated with LD treatment. Advanced PD patients often take up to 8-10 LD doses a day, trying to stabilize their motor conditions.
For these reasons, numerous efforts have been made by many pharmaceutical companies over the years to develop an effective long-acting LD. Available controlled-release preparations of LD currently on the market do not maintain sufficiently high LD plasma levels. The reason is that in addition to its very short half-life (90 min), LD is absorbed mainly in the upper part of the GI tract. Once a typical controlled-release formulation has passed the drug's narrow absorption window in the upper part of the GI, the drug is no longer absorbed in the distal intestine, regardless of the manner it is released from the dosage form.
Another concern with current LD treatment is that rapid elimination of LD and lack of means to sustain relevant LD levels for prolonged time intervals lead to the absence of sufficiently high LD plasma levels in patients in the morning, causing movement arrest and necessitating ultra-rapid LD dosage forms, generally unavailable on the market, or parenteral preparations which are cumbersome for self administration in deep OFF state.
The symptoms of PD in patients are frequently expressed as Unified Parkinson's Disease Rating Scale (UPDRS) score. Most frequently, so-called “part 3” is used in evaluation by a clinician of motor abilities/impairment of PD patients. The UPDRS was recently reviewed and updated, and is regarded as a standard mean to evaluate PD patients (see Movement Disorders, Vol. 22, No. 1, 2007, pp. 41-47; Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, Format, and Clinimetric Testing Plan, by Dr. Christopher G. Goetz et al, doi: 10.1002/mds.21198).
It is postulated that gastric retention could significantly prolong the LD's absorption phase, by retaining the drug in proximity to its absorption site and releasing the drug in a continuous manner, towards that absorption site. Some examples of gastroretentive LD delivery systems are disclosed in WO2009/144558 (Intec Pharma), which is herein incorporated by reference in its entirety. These gastroretentive formulations are also frequently referred to as “Accordion Pill”, or AP. Alternatively, some gastric retentive pharmaceutical compositions for treatment and prevention of CNS disorders are disclosed in WO2010/019915 (Depomed).
Hence, the challenge is to develop an oral, effective long-acting LD regimen that provides significantly more continuous and stable relevant LD plasma levels over 24 hours, with reduced Total OFF Time and significantly reduced doses per day, preferably a twice-daily dosing.